Drug list Flashcards
Paracetamol
Drug class: NSAID
Indication: pain, fever
Contraindications:
Side effects:
Amoxicillin
(ANTIBIOTIC CHOICE FOR PREGNANT WOMEN)
Drug class: Penicillin antibiotic (Broad Spectrum)
Indication: Treatment of infections.
H. pylori infections - Peptic ulcers
Haemophillius influenza - Resp infections and Pneumonia
Salmonella, Listeria Sp. -
Diarrhea
Used for infections caused by gram positive and gram negative bacteria
Mechanism of action:
-inhibits penicilin binding protein/DD Transpeptidase
- stops glycosyltransferase and transpeptidase reactions
- which stops to the crosslinking of D-alanine and D-aspartic acid in bacteria walls
Contraindications:
- allergic to penicillin (anaphylaxis)
Side effects: diarrhoea and nausea
SAFE FOR PREGNANCY
Cefuroxime
Drug class:
2nd generation Cephalosporin Antibiotic
Indication: Treat bacterial infections e.g. bronchitis, sinusitis
Mechanism:
- beta-lactam antibiotic
- binds to PBPs (penicillin - binding proteins) located inside the bacterial cell wall
- inhibits third and last stage of bacterial cell wall synthesis
Benzylpenicilin
Drug class: Antibiotic
Indication: bacterial infections
Mechanism:
- binds to PBPs (penicillin - binding proteins) located inside the bacterial cell wall
- inhibits third and last stage of bacterial cell wall synthesis
Oxytetracycline
Drug class: Tetracycline antibiotic
Indication: infections caused by gram positive and gram negative bacteria
Mechanism:
- inhibits cell growth by inhibiting translation
- binds to 30s ribosome subunit and prevents amino-acyl tRNA from binding to the A site of the ribosome.
Erythromycin
Drug class: macrolide antibiotic
Indication:
- bacteriostatic drug
- against infections
Mechanism: Inhibits protein synthesis by binding to the 23S ribosomal RNA molecule and 50S subunit
Contraindicated: in people with liver disease (hepatotoxicity) because of cytochrome p450.
Gentamycin
Drug class: aminoglycoside antibiotic
Indication: bacterial infections
Mechanism:
- bactericidal
- passes through gram-negative membrane in an oxygen-dependent active transport
Rifampicin
Drug class: Antibiotic
Indication: TB infections
Mechanism: Inhibition of DNA-dependent RNA polymerase leading to suppression of RNA synthesis and cell death
Trimethoprim
Drug class: antifolate antibiotic
Indication:
- used in combination with sulfamethoxazole
- uncomplicated urinary tract infections
Mechanism:
- is a reversible inhibitor of dihydrofolate reductase
which converts DHF (dihydrofolic acid) into THF (tetrahydrofolic acid)
- THF is necessary for the biosynthesis of bacterial nucleic acids
Sulfamethoxazole
Drug class: sulfonamide antibiotic
Indication:
-given in combination with trimethoprim
- treats infections (mainly UTI)
Mechanism:
- Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for bacterial conversion of PABA to dihydrofolic acid
-inhibits bacterial dihydrofolic acid synthesis due to its similarity to PABA (para-aminobenzoic acid)
- Most bacteria meet their need for folic acid by synthesizing it from PABA,
Vancomycin
Drug class: glycopeptide antibiotic
Indication: used to treat severe but susceptible bacterial infections such as MRSA
Mechanism:
- inhibition of cell wall biosynthesis
- Vancomycin forms hydrogen bonds with the terminal D-alanyl-D-alanine moieties of the NAM/NAG-peptides, preventing the incorporation of the NAM/NAG-peptide subunits into the peptidoglycan matrix
Colistin
Drug class: polymyxin antibiotic
Indications: bacterial infections caused by gram negative bacteria
Mechanism of action: disrupts the bacterial cell membrane
Ciprofloxacin
Drug class: second generation fluoroquinolone
Indication: bacterial infections
Mechanism of action:
- acts on bacterial topoisomerase II ( DNA gyrase) and topoisomerase IV
- Ciprofloxacin’s targeting of the alpha subunits of DNA gyrase prevents it from supercoiling the bacterial DNA which prevents DNA replication
Fusidic acid
Drug class: topical antibacterial
Indications:
-used to prevent and treat mild to moderate skin infections
Mechanism:
- bacteriostatic antibiotic
- fusidic acid works by interfering with bacterial protein synthesis
- prevents the translocation of the elongation factor G (EF-G) from the ribosome.
- It can also inhibit chloramphenicol acetyltransferase enzymes.
Antiherpes medications
- specific antiviral medications are used to treat herpes. These are called anti-herpes medications.
These antivirals can be used to treat:
- Herpes infections (caused by Herpes Simplex Virus)
- Varicella Zoster Virus (VZV)
- Cytomegalovirus (CMV)
Antiherpes medications can be split into two categories:
- Guanosine analogs
- viral DNA polymerase inhibitors
HSV (herpes simplex virus)
- HSV infects skin and mucosal epithelial cells
- There are two types of HSV: HSV1 and HSV2
HS1: generally causes infections above the waist:
- lips: herpes labialis
-mouth and gums: gingivostomatitis
- rare cases it can spread to the esophagus: esophagitis
- rare case spread to CNS: meningitis or encephalitis
HS2: infections below the waist
- genital organs: herpes genitalis
- HSV can pass from a mother to a baby when the baby passes through the infected maternal vaginal secretions and this can cause severe NEONATAL INFECTIONS.
HSV presentation
- small painful fluid filled blisters -ooze and ulcerate. Heal after a few weeks
- HSV also infects the nearby sensory neurons, which aren’t destroyed, but instead, they become a permanent home for the herpes virus. This is referred to as the latent phase of the infection and is typically asymptomatic.
- From time to time the herpes virus uses sensory neurons to produce copies of itself and these are released and infect epithelial cells.
Varicella Zoster Virus
- Varicella Zoster Virus causes a primary infection called varicella or chickenpox
- Chickenpox: a rash on the scalp, face, and trunk that contains macules, papules, vesicles, and scabs at the same time.
- From the neurons in the skin, VZV travels retrogradely to the nerve ganglia, where it remains dormant. Later on, if the immune system weakens, due to aging, stress, or immunosuppressive therapy, the virus can be reactivated.
- It can then travel back up through the sensory nerves, anterogradely to the skin and cause an infection in the innervated dermatome - that’s called herpes zoster or shingles.
Cytomegalovirus (CMV)
- CMV causes mononucleosis aka ‘mono’
Mono:
- sore throat
- lymphadenopathy
- fever
- malaise
- headache
symptoms resolve over a few weeks
- Now, in immunocompromised individuals, CMV can cause more severe infections including pneumonia, esophagitis, and retinitis which can lead to vision loss.
- CMV can also pass from a mother to a baby via the placenta causing a potentially life-threatening congenital infection.
Aciclovir (Acyclovir)
-Once they’re inside an infected cell acyclovir is phosphorylated to a monophosphate form by a viral enzyme, which is called viral kinase.
-acyclovir is converted to the acyclovir monophosphate by the viral thymidine kinase,
-Next, the monophosphate form is phosphorylated twice to the active triphosphate form by cellular enzymes.
-This triphosphate form acts as a guanosine analog which means that it’s similar in structure with the normal guanosine nucleotide.
-When this analog is inserted into the replicating viral DNA, it causes the growing DNA chain to terminate and DNA synthesis is halted.
Aciclovir
Drug class: Guanosine analog
Indication:
- used to treat herpes simplex, varicella zoster, herpes zoster.
- topical cream: indicated to treat recurrent herpes labialis (patients who are 12 yrs and older).
-tablets
- used to treat mild mucocutaneous lesions
- genital lesions
- herpes prophylaxis in immunocomprimised individuals.
Mechanism:
- Acyclovir becomes acyclovir monophosphate due to the action of viral thymidine kinase.
- Acyclovir triphosphate has higher affinity for viral DNA polymerase than cellular DNA polymerase and incorporates into the DNA where the missing 2’ and 3’ carbons causes DNA chain termination.
Side effects:
Malaria
- plasmodium gets into the bloodstream - it infects liver cells and red blood cells - which causes a variety of symptoms and sometimes even leads to death.
- medications: antimalarials
How malaria is spread:
- in mosquito gut - sporozoite
- sporozoites travel to liver and invade hepatocytes
- Schizogony (asexual reproduction) in hepatocytes.
- Merozoites released into blood
ERYTHROCYTIC PHASE:
- merozoites invade RBCs
- inside RBC- Plasmodium feeds on hemoglobin via a process called endocytosis. Plasma membrane around hemoglobin - called a food vacuole - where hemoglobin can be broken down
- Plasmodium uses the GLOBIN PROTEINS to fuel their growth, but the heme is toxic to them, so they are converted into insoluble HEMOZOIN CRYSTALS
- As the parasite feeds, it undergoes mitosis and differentiates into lots of merozoites, which then burst out of the red blood cell and enter back into circulation.
GAMETOGENIC PHASE:
- they divide and give rise to gametocytes, which are little sausage -shaped sexual forms that can be either male or female
- These gametocytes remain inside of a red blood cell, and can get sucked up by another female mosquito that bites the same malaria carrier.
- SPOROGONY (sexual reproduction): The gametocytes can then fuse together inside the mosquito to form a zygote.
- zygote - ookinete - oocyst ruptures in mosquito gut releases thousands of sporozoites
Malaria
- Fever in bursts due to TNF a and other inflammatory cytokines being released.
RBC destroyed:
- hemolytic pneumonia
- fatigue
- headaches
- jaundice
- splenomegaly
Quinine
These medications work by entering the plasmodium and accumulating in their food vacuoles.
Here, they bind to heme and prevent it from being converted into hemozoin.
Since heme is toxic to the Plasmodium, this eventually leads to their death
Quinine
Drug class: Alkaloid
Indication:
- used to treat uncomplicated plasmodium falciparum malaria (MALARIA)
Mechanism:
- drugs interfere with the parasite’s ability to break down and digest hemoglobin
- heme toxic to plasmodium - dies
Artemisinin derivatives
-These medications build up in the food vacuoles of the Plasmodium, where they bind to the iron found in heme and create free radicals that damage parasite proteins.
-They are especially useful since they are effective against all Plasmodium species, including the strains that are resistant to chloroquine and other quinoline derivatives.
-Their effectiveness is so high that they are considered the first choice for chloroquine resistant malaria.
Aremether aka Artemisinin
Drug class: antimalarial agent
Indication:
- used in combination with lumefantrine
- treat acute uncomplicated malaria
caused by Plasmodium falciparum.
Mechanism of action:
- interaction with ferriprotoporphyrin IX or ferrous ions in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species
Side effects:
Chloroquine
Drug bank: antimalarial drug
Indication:
- Infections with P.vivax, P. malariae, P. ovale and P.falciparum.
Mechanism of action:
-inhibits the action of heme polymerase in malarial trophozites, preventing the conversion of heme to hemazoin.
- Plasmodium species continue to accumulate toxic heme, killing the parasite.
Amprenavir
Drug class: protease inhibitor
Indication: treat HIV -1 (Virus Type -1 )
Mechanism:
- inhibits the HIV viral proteinase enzyme
- which prevents cleavage of the gag-pol polyprotein
- results in noninfectious immature viral particles
Reverse transcriptase inhibitors
- Reverse transcriptase inhibitors are an important part of HAART.
- HAART combination of medications used in the treatment of AIDS.
- AIDS is caused by a RNA containing retrovirus - HIV.
- retro - refers to it needing to use an enzyme called reverse transcriptase to transcribe a piece of “proviral” DNA from its RNA
- transcriptase inhibitors go and inhibit this enzyme, and prevent HIV replication.
- Based on their structure, they can be classified into nucleoside reverse transcriptase inhibitors, or NRTIs; and non-nucleoside reverse transcriptase inhibitors, or NNRTIs.
NRTI
- NRTIs resemble nucleosides, which are tiny molecules which when attached to a phosphate group give rise to nucleotides, which are building blocks of nucleic acids like DNA and RNA.
- HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have a molecule called CD4 on their membrane.
- HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope.
- NRTIs part of HAART. So typically you use two NRTIS and another antiretroviral which acts by a different mechanism.
-NRTI are also used alone in post-exposure prophylaxis, for example, in individuals who’ve recently been exposed to HIV infected blood in the past 72 hours.
-They can also be used in children born to HIV infected mothers who are at the risk of developing the disease.
HIV attack
- HIV contains nucleocapsid which is a capsule containing single stranded RNA, REVERSE TRANSCRIPTASE and INTERGRASE (enzymes)
- HIV binds releases reverse transcriptase into host cell
- RT uses the single stranded viral RNA as a template, and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA,
Proviral just means that it’s ready to be integrated into the host’s DNA. So it enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into new viruses, - immune cd4 cell activated start transcribing and translating proteins needed for the immune response.
- Over time, more and more immune cells are infected, and the immune system begins to fail which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off.
- These complications are referred to as AIDS
NRTI
- So, when an NRTI molecule enters the cell, it gets phosphorylated, or a phosphate group is added, and it will resemble a nucleotide.
-This fake nucleotide molecule now competes with the natural nucleotide in the infected cell for the attention of reverse transcriptase.
-If it’s picked and inserted into the proviral DNA, it will screw up HIV’s entire plan.
-Think of DNA like a written instruction for synthesizing proteins, and the nucleotides are the letters.
-The NRTI molecule are like random foreign letters that disrupts the instruction so viral proteins can’t be made.
-Also, additional nucleotides can not be added to the NRTI molecules inserted into the proDNA so this stops its synthesis.
-So instead of the proviral DNA, what we end up with are a bunch of incomplete instructions full of gibberish.
- This stops new viruses from being created and keeps other CD4+ cells from getting infected.
However, it’s important to note that NRTIs have no effect on the completed proviral DNA already incorporated into the CD4+ cells, and the cells that are already infected remain infected.
- So, NRTIs can only slow down the progression of the disease, but not cure it.
Nystatin
Drug class: polyene ionophore antifungal
Indication:
-used to treat cutaneous, mucocutaneous and gastrointestinal mycotic infections, particularly those by candida infections
Mechanism of actions:
- channel forming ionophore
- The formation of this pore results in a change in membrane permeability that allows for leakage of intracellular contents and the subsequent disruption of electrochemical gradients necessary for proper cell function
Amphotericin
Drug class: antifungal
Indications:
- given as an injection
- used to treat life threatening fungal infections
- treats fungal infections in neutropenic patients, cryptococcal meningitis in HIV infection, fungal infections and leishmaniasis
Mechanism of action:
- Amphotericin B is a fungistatic or fungicidal depending on the concentration obtained in the body fluids and the susceptibility of the fungus.
- Drug binds to ergosterol in the cell membrane, which creates a transmembrane channel, change in permeability allowing leakage of intracellular components.
Griseofulvin
Drug class: Antifungal agent
Indication:
- oral form only (not applied topically)
- treats a variety of superficial tinea infections and fungal infections of the fingers and toes
- ringoworm infection of the skin, hair and nails namely: tinea corporis, tinea pedis, tinea cruris, tinea barbae, cradle cap
Mechanism:
- griseofulvin is fungistatic
-interferes with spindle and cytoplasmic microtubules by binding to alpha and beta tubulin
- thought to inhibit fungal cell mitosis and nuclear acid synthesis
- binds to keratin in human cells, once it reaches fungal site of action, it binds to fungal microtubes thus altering the fungal process of mitosis
DNA alkylating medication
- Alkylating agents attach an alkyl group at the number 7 nitrogen atom of guanine.
- Now repair enzymes recognize that something is wrong, so they attempt to replace the alkylated bases and cause fragmentation of the DNA, or DNA strand breakage
- When this section of the DNA is repaired, abnormal base pairing could result, like having a thymine paired up with guanine instead of the usual cytosine.
- Eventually, the DNA damage results in cell death
Alkylating agents can also cause damage through the cross linking of DNA
- Now, another mechanism by which alkylating agents cause DNA damage is the crosslinking of DNA.
- In this process, an alkylating agent has two DNA binding sites causing two guanine bases to link together, forming a covalent bond, leading to the formation of cross-bridges.
- Cross-linking prevents DNA from being separated for replication or transcription, again eventually resulting in cell death
- DNA alkylating medications are cell cycle-nonspecific agents, meaning they act on tumor cells during all phases of the cell cycle, including the resting G0 phase.
Cyclophosphamide
- 1st IV chemotherapy
- pro drug - administered in inactive form and need to be metabolized into an active form by the liver enzyme cytochrome p450.
Side effects:
- depress bone marrow function - aplastic anemia
- most significant risk of developing leukemia or other malignancies after prolonged use
- hair loss
- GI disturbances
- depression of gametogenesis ( infertility)
- teratogens ( disrupt fetal growth) - birth defects
- bladder cancer
- hemorrhagic cystitis ( can be reversed by taking fluids and sulfhydryl donors )
- SIADH
Cyclophosphamide
Drug class: chemotherapy drug / nitrogen mustard
Indication:
-lymphoma
- multiple myeloma
- leukemia
- ovarian cancer
- breast cancer
- small lung cancer
- neuroblastoma
- sarcoma
Mechanism of action: DNA Alkylation -> DNA crosslinking -> decreased DNA replication
Side effects: - hemorrhagic cystitis (bleeding in bladder)
What happens to cancer cells after uncontrolled growth begins
- As cancer cells start piling up on each other, they form a small tumor mass and they need to induce blood vessel growth, called angiogenesis, to supply themselves with enough energy.
- Some tumors produce vascular endothelial growth factor, or VEGF, which binds to VEGF receptors found on vascular endothelial cells and stimulates angiogenesis.
- Also, many tumors overexpress growth factor receptors like the epidermal growth factor receptor, or EGFR, and the human epidermal receptor 2, or HER2, that stimulate cell proliferation and tumor growth.
- Malignant tumors are ones that are able to break through the basement membrane.
- Some of these malignant tumors go a step further and detach from their basement membrane at the primary tumor site, enter nearby blood vessels or the lymphatic system, and establish secondary sites of tumor growth throughout the body—a process called metastasis.
When monoclonal antibodies bind
- Now, the monoclonal antibodies that are used for the treatment of cancer target specific antigens that are usually overexpressed on the surface of cancer cells.
- Once these antibodies bind to the surface of cancer cells, they can trigger apoptosis, promote the formation of MAC complexes which trigger complement-mediated cell lysis, or attract other immune cells to attack the cancer cells.
- Furthermore, a lot of these antigens are actually the cell receptors that promote growth and proliferation.
- So when the monoclonal antibodies bind, they prevent these receptors from functioning.
- Monoclonal antibodies are all takes intravenously because they are proteins and would be destroyed in the GI tract if taken perorally
Nomenclature of monoclonal antibodies
- all have the suffix ‘-mab’
- if its a human antibody has the suffix ‘-umab’
- Now, there are also chimeric monoclonal antibodies which means that they have both human and non-human components, such as mouse components.
These antibodies have the suffix “-ximab”, with a “xi” before the “mab”, like rituximab and cetuximab.
They’re more likely to be recognized as foreign, leading to hypersensitivity reactions like skin rashes, pruritus, headache, fever, and hypotension.
- Finally, there are humanized monoclonal antibodies which are produced by non-human species, such as mice, but they have been humanized, or modified to look similar to those produced by humans.
- Humanized antibodies have the suffix “-zumab”, with a “zu” before the “mab”, like bevacizumab, and they’re less likely to cause hypersensitivity reactions than the chimeric antibodies.
Rituximab
-binds to cd20 (antigen found on b-cell membranes)
- causes cell death through multiple mechanisms
- First it activates the complement system initiating the formation of the membrane attack complex that creates holes on the cell membrane, ultimately leading to cell lysis.
-Also, rituximab induces apoptosis, or programmed cell death.
-In addition, rituximab activates antibody-dependent cell-mediated cytotoxicity, where the bound antigen-antibody complex gets recognized by immune cells called natural killer cells, which form pores in the cell that allow the entry of enzymes that work like silent assassins to cause cell death.
Indicators:
- The CD20 antigen is found on both normal and malignant B cells, so rituximab is used primarily for the treatment of non-Hodgkin B cell lymphomas.
- It’s also indicated for chronic lymphocytic leukemia, or CLL, where there is abnormal proliferation of lymphocytes including B cells.
- Aside from cancer, it’s also useful for treating autoimmune diseases where there is abnormal activation of the immune cells like in rheumatoid arthritis.
- Rituximab is also used for the treatment of idiopathic thrombocytopenic purpura, or ITP, where B cells produce antibodies that destroy platelets.
Rituximab side effects
The bad news is that rituximab can cause hypersensitivity reactions because it’s a chimeric antibody like cetuximab.
Other side effects include suppression of the immune system and reactivation of viruses such as JC virus, or John Cunningham virus.
This particular virus causes a demyelinating disease of the central nervous system called progressive multifocal leukoencephalopathy, or PML and is potentially life threatening.
Anthracyclines indications and side effects
- Indications for anthracyclines include the treatment of solid tumors like breast, thyroid, lung, and ovarian cancers, but also leukemias and lymphomas.
- Now an important side effect of these medications is cardiotoxicity due to the buildup of free radicals in the myocardium.
- Cardiotoxicity manifests as dilated cardiomyopathy that is lifetime dose dependent and irreversible when it happens.
- But the good news is that cardiotoxicity can be prevented with dexrazoxane, which is an iron chelating agent that binds to iron in the myocardium and prevents the production of free oxygen radicals. Other side effects include myelosuppression and alopecia.
TAXANES - microtubule inhibitors
- example paclitaxel
- They enhance tubulin polymerization into protofilaments and microtubules, but they also bind directly to the spindle fibers and stabilize them.
- So they act like cement that overstablizes the microtubules and prevents them from depolymerizing and breaking down.
- This is a problem because the microtubules need to break down during anaphase so the cell can divide.
So, taxanes are also cell-cycle specific and act on M phase.
Paclitaxel
- impaired degradation of polymerized microtubules
- ## overstabalising (hypertables) microtubules so you cant break down microtubules in mitosis
Tamoxifen
Drug class: SERM ( selective estrogen receptor modulator). Certain tissue its a agonist and antagonist in other tissue
Mechanism:
5-fluroracil is an antimetabolite
- 5-fluorouracil is a pyrimidine analog that interferes with folic acid cycle.
- 5-fluorouracil gets metabolized to its active form which is 5-FdUMP and forms a complex with THF.
- This complex can inhibit thymidylate synthase which normally binds to dUMP and converts it to dTMP.
- Inhibition of thymidylate synthase results in decreased synthesis of thymidine which is a DNA component.
- Other active metabolites of 5-fluorouracil can also be incorporated into DNA and RNA resulting in inhibition of DNA and RNA synthesis.
5-flurororacil (aka 5FU)
Drug class: chemotherapy
Administration: intravenously
Indication:
only used for solid tumors not hematological
- colorectal cancer
- esophageal cancer
- stomach cancer
- pancreatic cancer
- breast cancer
- cervical cancer
Mechanism:
- inhibits the process of pre-rRNA into mrRNA
- disrupts post transcriptional modification tRNAs
- inhibits the assembly activity of snRNA/protein complexes thereby inhibiting splicing of premRNA
Topoisomerase inhibitors
- act by blocking the enzyme topoisomerase
- used as anticancer agents that target specific phases of the cell cycle
- during DNA replication, we unzip the double helix with the enzyme DNA helicase and this creates a replication fork, with the two prongs of the fork represented by the two strands that are separated from one another.
- DNA helicase unzips the DNA, the segments of DNA ahead of it start to overwind - meaning, the double helix becomes more tightly wound
- Overwinding of the DNA can slow down replication, so the enzyme DNA topoisomerase works ahead of DNA helicase to loosen up the tight DNA coils.
- It achieves this by gently snapping one strand, loosening the overwinding tension, and then patching it back up, tension free.
Topoisomerase inhibitors
-Topoisomerase inhibitors are meant to interfere with both types of DNA topoisomerases, called topoisomerase I and II.
-Topoisomerase I cuts one of the two strands of the double-stranded DNA during replication, while Topoisomerase II cuts both strands.
-If we disable these enzymes, DNA will overwind just like a rubber band, until it tears itself apart, leading to cell death.
PODOPHYLLOTOXINS
- Etoposide
- induce DNA breakage through inhibition of topoisomerase II
-
Etoposide
topisomerase II causes double breaks in the DNA strand
Mechanism: Inhibition of topoisomerase II which decreases DNA unwinding
Microtubule inhibitor: vinblastine
There are two groups of microtubule inhibitors:
- Vinca alkaloids
- Taxanes
- Vinblastine is a vinca alakloid
- Vinca alkaloids bind to β-tubulin and block its polymerization into protofilaments, which form microtubules, centrioles, centrosomes, and spindle fibers.
- This means the cell can’t form stable mitotic spindles and will stop at metaphase.
-So, vinca alkaloids act in the M phase of the cell-cycle and are cell-cycle specific.
Vinca alkaloid side effects
-Vinca alkaloids disrupt the progression of mitosis in all rapidly dividing cells in the body including hair follicles and gastrointestinal epithelium, so vinblastine and vincristine cause alopecia, or loss of hair, and gastrointestinal symptoms.
-In addition, they are associated with bone marrow suppression since the cells here are constantly making the platelets, red, and white blood cells.
-Now, vinblastine causes more bone marrow suppression, but vincristine is more neurotoxic as it interferes with microtubule polymerization in neuronal axons disrupting the neuronal activity.
-Neurotoxicity usually manifests as peripheral neuropathy causing symptoms like a decrease in sensation in the toes and fingers, sometimes called a glove and stocking distribution, as well as autonomic nervous system malfunction with orthostatic hypotension, urinary retention, and constipation.
Vinblastine
Method: impaired polymerization of microtubules. Cannot form microtubules correctly
Cisplatin
Method of action: alkylating agent -> DNA cross linking
Antimetabolite
- Alright, now the cancer cells pretty much do nothing but divide all day long and so they are very sensitive to cytotoxic medications that block DNA synthesis.
-The bad news is that plenty of normal cells in our body, like the cells lining the GI tract, and the precursors to blood cells and platelets, are also actively dividing and this explains why anticancer medications are toxic to these tissues.
So the antimetabolites usually disrupt the pathway responsible for DNA synthesis by mimicking nucleobases or folic acid, and cause DNA replication and cell proliferation to come to a halt.
Medications that mimic purine include azathioprine and cladribine, while medications that mimic pyrimidine include cytarabine and 5-fluorouracil. Finally, there’s folic acid analogues like methotrexate.
Methotrexate
Finally, an important antimetabolite is methotrexate which is a folic acid analog.
Alright, DHFR normally converts DHF to THF which provide methyl groups necessary for the synthesis of dTMP from dUMP and for purine synthesis.
Now methotrexate has a higher affinity for DHFR, than DHF and so it binds and irreversibly inhibits this enzyme.
THF is also involved in synthesis of purines and amino acids as well. The result is a decrease in synthesis of DNA, RNA, and proteins and thus, inhibition of cell division.
Methotrexate
- inhibits dihydrofolate reductase
- inhibition of the s-phase
